Immunocompromised patients demonstrate a wide variety of idiopathic cutaneous and mucosal lesions including dermatitis, gastrointestinal and genital tract ulcerations, and recurrent aphthous stomatitis. One objective of this research program is to evaluate the pathogenesis of mucosal inflammation associated with immune dysregulation in HIV-infected patients with aphthous lesions. A randomized, controlled clinical trial using topical thalidomide was initiated which serves as a vehicle for several lines of inquiry directed towards investigating the pathogenesis and treatment of oral aphthous ulcers, which are spontaneous, recurrent mucosal ulcerations of unknown etiology, and which are persistent and debilitating in persons with HIV/AIDS.Dose related healing in response to topical thalidomide without adverse effects. Based on the impressive healing response, topical thalidomide appears to be an effective alternative to oral thalidomide treatment for aphthous ulcers in patients with HIV infection. In addition to mucosal lesions, cutaneous lesions may also become chronic and debilitating, and efforts are focusing on characterizing the underlying pathogenesis. The delayed cutaneous healing response in the aged, characterized by a predominance of neutrophils and excess elastase, can be mimicked in animal models including ovariectomized rodents and secretory leukocyte protease inhibitor(SLPI) knockout mice. Using these models of cutaneous and oral wounds, delayed healing can be reversed by the topical application of TNF antagonists, SLPI and synthetic fibronectin peptides. Based on the successful topical delivery of these and other agents in reversing human nonhealing wounds, other novel approaches for inhibiting the persistent leukocyte recruitment and overabundant elastase released at the inflammatory site will be evaluated for their efficacy in facilitating the healing process.